Research update is published by the Butler center for Research to share significant scientific findings from the field of addiction treatment research. researChupDAte Butler Center for researCh OctOBeR 2012 Drug Abuse, Dopamine, and The hazelden experience the Brain’s Reward System Upon entering treatment many patients show signs of impaired cognitive function such as poor problem Advances in neuroscience, psychology, and biology have shed light on the ways that long-term use solving skills; however, these impairments improve of alcohol and other drugs change the brain to foster continued and chronic patterns of compulsive during abstinence and treatment. Hazelden uses a drug abuse. these efforts have not only helped redefine addiction as a disease but have increased our comprehensive abstinence-based Twelve Step treatment understanding of the underlying neurobiology that influences the progression from casual first-time use to approach that incorporates cognitive-behavioral and chronic abuse that often leads to harmful, long-term consequences. the understanding of the effects of group therapy to promote recovery from the long-term these substances on key brain areas throughout this progression has informed and guided behavioral and consequences of drug abuse. pharmacological treatments, further defining addiction as a treatable disease. At the Butler Center for Research, studies are currently the Brain following Initial and early substance use underway to assess cognitive processing of alcohol- Individuals use drugs of abuse for a variety of reasons, but the euphoric feelings and intense pleasure related cues in individuals with alcohol dependence in associated with being “high” are the most frequently reported.1 It has long been established that this feeling hopes of better understanding the cognitive factors that is due to the drugs effect on brain areas that regulate and reinforce natural rewards that are vital to our influence vulnerability to relapse. existence, such as food and sex.2 these brain areas, collectively referred to as the brain’s reward system (or the mesolimbic dopamine system), are connected by neurons (i.e., brain cells) that originate in a structure cOnTrOVerSieS & QUeSTiOnS deep within the brain called the ventral tegmental area. Dopamine released by the ventral tegmental area How long does cognitive impairment due to drug acts as a chemical messenger that signals the activation of neurons located in the nucleus accumbens, a abuse last? structure often referred to the brain’s “pleasure center” due to its influence on motivation and reward.3 Researchers have demonstrated that activation of the nucleus accumbens allows us to predict whether All drugs of abuse, when taken for extended periods something will be rewarding or pleasurable.4 of time, produce long-term dysfunction in the way the Animal and human studies have brain processes information, and the severity of the the Brain’s reward system demonstrated that the nucleus accumbens dysfunction is related to the frequency and duration of prefrontal activates when exposed to natural life- drug use. Over time, abstinence and active participation cortex Ventral sustaining rewards, such as when food in treatment programs can drastically improve cognitive tegmental is presented while in a state of hunger.5, 6 function impairments related to prolonged drug abuse. Area Nearly all drugs of abuse increase dopamine in the nucleus accumbens, and they do so Why are drugs more addictive than natural rewards? Nucleus with greater efficiency and more prolonged Drugs of abuse can release approximately 2 to 10 times Accumbens effects than natural rewards.7 the amount of dopamine compared to natural rewards and are therefore more effective in stimulating the the Brain following Chronic and brain’s reward system. The effects of drugs of abuse long-term substance abuse can also be immediate (e.g., when smoked or injected) the activation of the ventral tegmental area and are longer lasting than the effects produced by and the resulting flood of dopamine within behaviors that are naturally rewarding. The efficiency of the nucleus accumbens are the first steps of initial drug use that can eventually lead to the chronic and drugs of abuse in activating the reward system results compulsive patterns that define drug abuse. Recent research with humans using the latest brain imaging in strong motivation to continue to take drugs and a technology has increased our understanding of the neurobiology underlying this important transition. lack of motivation to engage in behaviors that are not Following repeated drug use that produces unnaturally high levels of dopamine within the reward system, drug related. the brain adapts by decreasing the number of receptors that dopamine specifically targets (i.e., dopamine receptors).9 there are several types of dopamine receptors, and all are important to healthy brain function, but the one most consistently associated with drug abuse is the dopamine receptor called D2R.9 Results from research using pet imaging have demonstrated significant reductions of D2R in the reward system of individuals with substance abuse problems.9 Researchers reason that the reduction in D2R following long- term drug use can eventually result in a state of anhedonia, which is characterized by a lack of enjoyment in activities that were previously enjoyable such as socializing with friends and family or engaging in healthy non-drug-related activities.10 these individuals may feel compelled to take drugs just to relinquish this anhedonic state and approximate normal reward system function.7 > cONtINueD ON BAcK < cONtINueD FROM FRONt Drug Abuse, Dopamine, and the Brain’s Reward System the reduction of D2R is associated with dysfunction of an additional structure in the brain’s reward system. the prefrontal cortex is located at the forefront of the brain and, like the nucleus accumbens, its activation is modulated by the dopamine it receives from the ventral tegmental area.11 However, unlike the nucleus accumbens, the role of the prefrontal cortex is to evaluate reward impulses and references determine whether they are safe to pursue.11 In a sense, the prefrontal cortex exerts parental control 1. Wise, R. A. (2009). Roles of nigrostriatal—not just mesocorticolimbic- over the brain’s reward system so that the rewards that are pursued are safe and beneficial to dopamine in reward and addiction. Trends Neurosci, 32, 517-524. 2. Anselme, P. (2009). The effect of exposure to drugs on the processing sustaining life. Research has shown that problems within the prefrontal cortex are associated with a of natural rewards. Neurosci Biobehav Rev, 33, 314-335. lack of inhibitory control and forethought (i.e., impulsivity) in addition to poor decision making with 3. Carlezon, W. A. Thomas, M. J. (2009). Biological substrates of regard to the long-term consequences of behaviors.11 Researchers began investigating the role of the reward and aversion: nucleus accumbens activity hypothesis. Neruopharmacology, 56 (Suppl 1), 122-132. prefrontal cortex in drug abuse given the similarity between these maladaptive behaviors and the 4. Schultz, W. (2010). Dopamine signals for reward value and risk: basic compulsive drug taking that and recent data. Behav Brain Funct, 6, 24. occurs despite the resulting 5. Lawrence, N. S., Hinton, E. C., Parkinson, J. A., Lawrence, A. D. (2012). Dopamine D2 receptors are lower in substance abusers Nucleus accumbens response to food cues predicts subsequent snack adverse consequences in consumption in women and increased body mass index in those with individuals who have chronic reduced self-control. Neuroimage, 63, 415-422. substance abuse problems.11 6. Smith, K. S., Berridge, K. C., Aldridge, J. W. (2011). Disentangling pleasure from incentive salience and learning signals in brain reward circuitry. Proc Natl Acad Sci USA, 108, E255-E264. Results from imaging studies 7. National Institute of Drug Abuse (2010). Drugs, brains, and behavior: have demonstrated severe the science of addiction. Bethesda, Maryland: U.S. Department of dysfunction in the prefrontal Health and Human Services. cortex of individuals with 8. Volkow, N. D., Fowler, J. S., Wang, G. J., Baler, R., Telang, F. (2009). Imaging dopamine’s role in drug abuse and addiction. long-term substance abuse Neuropharmacology, 56 (Suppl 1), 3-8. problems,11 and more 9. Volkow, N. D., Wang, G., Fowler, J. S., Tomasi, D., Telang, F. (2011). recent studies have shown Addiction: Beyond dopamine reward circuitry. PNAS, 108, 15037- 15042. that the magnitude of this 10. Heinz, A., Siessmeier, T., Wrase, J., Buchholz, H. G., Grunder, G., dysfunction is correlated with Kumakura, Y., Cumming, P., Schreckenberger, M., Smolka, M. N., Rosch, F., Mann, K., Bartenstein, P. (2005). Correlation of alcohol substance abuse severity. craving with striatal dopamine synthesis capacity and D2/3 receptor Furthermore, evidence from availability: a combined [18F]DOPA and [18F]DMFP PET study of Source: NIDA, 2010 detoxified alcoholic patients. Am J Psychiatry, 162, 1515-1520. structural imaging studies 11. Goldstein, R. Z. Volkow, N. D. (2011). Dysfunction of the prefrontal indicates that the material cortex in addiction: neuroimaging findings and clinical implications. that primarily makes up the prefrontal cortex and is vital to its function (i.e., gray matter) is reduced by Nat Rev Neurosci, 12, 652-669. up to 20 percent in individuals with chronic substance abuse problems.15, 16, 17, 18 Data indicate that the 12. Sorg, S. F., Taylor, M. J., Alhassoon, O. M., Gongvatana, A., Theilmann, R. J., Frank, L. R., Grant, I. (2012). Frontal white matter integrity severity of gray matter reduction is associated with longer lifetime drug use and worse executive control predictors of adult alcohol treatment outcome. Biol Psychiatry, 71, 262-268. problems.13, 14 current theories of substance abuse suggest that motivation to take a drug is initially 13. Chanraud, S., Martelli, C., Delain, F., Kostogianni, N., Douaud, G., inhibited by the prefrontal cortex due to the perceived adverse consequences; however, as drug use Aubin, H. J., Reynaud, M., Martinot, J. L. (2007). Brain morphometry continues, the prefrontal cortex becomes less able to regulate activation of the reward system and drug and cognitive performance in detoxified alcohol-dependent with preserved psychosocial functioning. Neuropsychopharmacology, 32, use becomes compulsive despite the problems it may cause.19 429-438. 14. Chanraud, S., Pitel, A. L., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. treatment Implications (2010). Dual tasking and working memory in alcoholism: relation to frontocerebellar circuitry. Neuropsychopharmacology, 35, 1868-1878. Results from studies of the neurobiological effects of drugs have validated preexisting treatment 15. Makris, N., Oscar-Berman, M., Jaffin, S. K., Hodge, S. M., Kennedy, D. N., methods and informed the development of new strategies to form a multipronged approach to the Caviness, V. S., Marinkovic, K., Breiter, H. C., Gasic, G. P., Harris, G. .J. (2008). Decreased volume of the brain reward system in alcoholism. treatment of drug abuse. Intrinsic to this approach is a need to 1) decrease the reward value of Biol Psychiatry, 64, 192-202. drugs and increase the value of nondrug rewards, 2) weaken the drive that facilitates drug taking by 16. Schwartz, D. L., Mitchell, A. D., Lahna, D. L., Luber, H. S ., Huckans, abstaining from drug-related behaviors, and 3) strengthen the brains ability to control impulses to use M. S., Mitchell, S. H., Hoffman, W. F. (2010). Global and local morphometric differences in recently abstinent methamphetamine- drugs.8 evidence indicates that the brain is more resilient than previously thought and can recover from dependent individuals. Neuroimage, 50, 1392-1401. damage associated with long-term substance abuse. For example, the loss of D2R following heavy 17. Sim, M. E., Lyoo, I. K., Streeter, C. C., Covell, J., Sarid-Segal, O., Ciraulo, D. A., Kim, M. J., Kaufman, M. J., Yurgelun-Todd, D. A., methamphetamine use can recover over long-term abstinence,7 and active participation in cognitive Renshaw, P. F. (2007). Cerebellar gray matter volume correlates behavioral therapy has been shown to increase gray matter volume in the prefrontal cortex.20 thus, with duration of cocaine use in cocaine-dependent subjects. Neuropsychopharmacology, 32, 2229-2237. the brain can recover from the detrimental and long-term consequences of drug abuse given time 18. Yuan, Y., Zhu, Z., Shi, J., Zou, Z., Yuan, F., Liu, Y., Lee, T. M., Weng, X. and treatment. (2009). Gray matter density negatively correlates with duration of heroin use in young lifetime heroin-dependent individuals. Brain Cogn, 71, 223-228. 19. Everitt, B. J., Belin, D., Economidou, D., Pelloux, Y., Dalley, J. W., hazelden.org Robbins, T. W. (2008). Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction. Phils Trans R Soc Lond B Biol Sci, 363, 3125-3135. Butler Center for researCh OctOBeR 2012 20. de Lange, F. P., Koers, A., Kalkman, J. S., Bleijenberg, G., Hagoort, P., van der Meer, J. W. Toni, I. (2008). Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with The Butler Center for Research informs and improves recovery services and produces research chronic fatigue syndrome. Brain, 131, 2172-2180. that benefits the field of addiction treatment. We are dedicated to conducting clinical research, collaborating with external researchers, and communicating scientific findings. Justin J. anker, ph.d., research Scientist If you have questions, or would like to request copies of Research Update, please call 800-257-7800 ext. 4405, email [email protected], or write BC 4, P.O. Box 11, Center City, MN 55012-0011. © 2012 Hazelden Foundation Hazelden and the Hazelden logo are registered BcR-Ru16 trademarks of the Hazelden Foundation. 3984-4 (10/12)